Intermolecular oxyarylation of olefins with aryl halides and TEMPOH catalyzed by the phenolate anion under visible light

Article abstract of DOI:10.1039/d0sc02160a

The phenolate anion was discovered as a new photocatalyst with strong reduction potentials. Under visible light irradiation, the phenolate anion enabled the reduction of (hetero)aryl halides (including electron-rich aryl chlorides) to (hetero)aryl radicals through single electron transfer. Based on this new photocatalyst, a novel and efficient photocatalytic protocol for the intermolecular oxyarylation of olefins with aryl halides and TEMPOH was developed. The developed three-component coupling reaction proceeded under redox-neutral reaction conditions with stable and readily available synthons and exhibited broad substrate scope. The utility of this process was further highlighted by the diversified chemical manipulation of the resulting oxyarylation products and the late-stage modification of active pharmaceutical ingredients.

Full text of DOI:10.1039/d0sc02160a

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ARTICLE
Intermolecular Oxyarylation of Olefins with Aryl Halides and
TEMPOH Catalyzed by Phenolate Anion under Visible Light
Kangjiang Liang, Qian Liu, Lei Shen, Xipan Li, Delian Wei, Liyan Zheng and Chengfeng Xia*
Received 00th January 20xx,
Accepted 00th January 20xx
The phenolate anion was discovered as a new photocatalyst with strong reducing potentials. Under visible light irradiation,
the phenolate anion enabled the reduction of (hetero)aryl halides (including electron-rich aryl chlorides) to (hetero)aryl
radicals through single electron transfer. On basis of this new photocatalyst, a novel and efficient photocatalytic protocol
for the intermolecular oxyarylation of olefins with aryl halides and TEMPOH was developed. The developed three-
component coupling reaction proceeded under redox-neutral reaction conditions with stable and readily available synthons
and exhibited broad substrate scope. The utility of this process was further highlighted by the diversified chemical
manipulation of the resulting oxyarylation products and the late-stage modification of active pharmaceutical ingredients.
DOI: 10.1039/x0xx00000x
arylstannanes,[6] or arylsilanes[7] were reported (Scheme 1a). In
addition, Meerwein-type radical oxyarylation methods have
been developed as an attractive alternative in recent years with
Introduction
Since the chemical reactivity of electronically excited
9]
aryl diazonium salts,[8] diaryliodonium salts,[8e,
or aryl
molecules differs fundamentally from that in the ground state,
the photochemistry induced by visible light provides fresh
opportunities to expand the potential of organic chemistry.
Various photocatalysts, including Ir or Ru complex and organic
dyes, have been developed and extensively explored.[1]
Phenolate anions are a useful model system for photoinduced
electron ejection mechanism studies.[2] Recent research
showed that phenolate anions acted as photoreductants to
activate perfluoroalkyl iodides in perfluoroalkylation reaction.[3]
We also discovered that the visible light-excited vinylphenolate
anions enabled the direct reducing aryl halides to aryl radicals.[4]
However, attempts to use the vinylphenolate anion as a new
photocatalyst failed and only afforded the Heck-type arylation
products by coupling with aryl radicals together. In this
manuscript, we discovered that a tri-substituted phenol anion
possessed strong reducing potential and enabled acting as a
new photocatalyst with redox-neutral features. To demonstrate
abilities of this new photocatalyst, we design an intermolecular
oxyarylation of olefins with aryl halides under visible light
irradiation.
hydrazines[10] as radical precursors (Scheme 1b). While
numerous advances have been made in this area, the ability to
access this molecular scaffold array with modular flexibility
remains limited. Requiring the use of toxic, unstable, or
unavailable aryl precursors has impeded the further adaptation
of these methods in the synthetic community. Furthermore, no
general protocol for oxyarylation of olefins with aromatic
heterocycle motifs which are essential in a wide range of
pharmaceuticals has yet been reported.
a
) Transition-metal catalyzed oxidative oxyarylation
R1O
Ar
[Pd] [Au]
or
Ar
+
R
stoichiometric
oxidant
R
X
X = B(OH)2, SnBu3, SiMe3
) Meerwein-type radical oxyarylation
TEMPONa
b
R1O
Ar
thermal induction
Ar
+
R
R
[Ir], hv
X
X = N2BF4, IArX, NH-NH2
c
(
) Phenolate catalyzed oxyarylation under visible light this work)
Phenolate
Photochemical
TEMPO
Catalyst
Ar
X
Ar
+
R
Intermolecular oxyarylation has attracted great attention
since one oxygen substituent and one aryl group add across an
olefin via vicinal difunctionalization process. In light of these
TEMPO-H, base
R
light, rt
X = I, Br, Cl
Scheme 1. Strategies for intermolecular oxyarylation of olefins. a, Transition-
benefits, transition-metal (Pd and Au) catalyzed oxidative metal catalyzed oxidative oxyarylation. b, Meerwein-type radical oxyarylation. c,
Phenolate catalyzed oxyarylation under visible light.
oxyarylation has been extensively studied and several protocols
for oxyarylation of olefins with arylboronic acids,[5]
In this context, a catalytic method for the direct
oxyarylation of olefins with (hetero)aryl halides which are the
cheapest and the most readily available arylation reagents
would circumvent these issues and greatly expand the scope of
aryl precursors. The single-electron reductive activation of aryl
halides by photoredox catalysis has been a powerful strategy for
aryl radical generation from stable starting materials.[11]
However, most of these methods require a large excess of
Key Laboratory of Medicinal Chemistry for Natural Resource (Ministry of
Education and Yunnan Province), State Key Laboratory for Conservation and
Utilization of Bio-Resources in Yunnan, and School of Chemical Science and
Technology, Yunnan University, 2 North Cuihu Road, Kunming 650091, China. E-
mail: xiacf@ynu.edu.cn
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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sacrificial electron donors which result in a fast competing a model reaction. The 4-phenylphenol derivativesVwiewerAerticclhe oOnsleinne
DOI: 10.1039/D0SC02160A
hydrogen atom abstraction by radical intermediates to deliver as catalysts. After irradiation with two 18 W blue light emitting
undesired side products and limit the choice of radical coupling diode (LED) lamps for 16 h, a promising lead result was observed
partners. Additionally, aryl chlorides without electron by using 4-phenylphenol (PC1) as catalyst in the presence of
withdrawing substituents are still a poorly accessible substrate TEMPOH and Cs2CO3 in DMSO, providing 40% yield of the
for currently known visible light photocatalysts due to their desired oxyarylation product 3 at room temperature (Table 1,
large negative reduction potentials.[12] Here, we demonstrated entry 1). Further screening of catalysts revealed that 2,6-di-tert-
the application of colored phenolate anion as new visible light butyl-4-phenylphenol (PC3) was the optimal catalyst for this
photocatalyst for the catalytic generation of (hetero)aryl protocol (entries 26), and the product 3 was obtained in 87%
radicals from non-activated (hetero)aryl halides and the yield (entry 3). Interestingly, catalysts with a bis-tBu system
successful development of an operationally simple and redox- (PC3-PC6) afforded higher yields compared to other tested (PC1
neutral protocol for the intermolecular oxyarylation of a wide and PC2). The redox reversibility observed by electrochemical
range of olefins (Scheme 1c).
measurements (see Supplementary Figure 5) suggested that the
introduction of bis-tBu remarkably prolongs the lifetime of
corresponding phenoxyl radicals. Therefore, we reasoned that
the steric hindrance of the bis-tBu system might be good for the
catalyst regeneration by improving the kinetic stability of the
phenoxyl radicals, thus leading to high efficiency. In an attempt
to seek better reaction conditions, a survey of other bases
(KHCO3, Na2CO3, K2CO3, K3PO4, DBU, and TMG) and solvents
(DMF, DMA, acetone, and CH3CN) indicated that they were not
comparable to the combination of Cs2CO3 and DMSO (see
Supplementary Table 1). Control experiments revealed that the
light, catalyst, and base were essential for this reaction (entries
79). Besides the bromobenzene 1b, the chlorobenzene 1c was
also efficiently activated for the oxyarylation, albeit moderate
Results and discussion
Details of our working hypothesis are described in Scheme
2. We envisioned that a photocatalytic cycle wherein a suitable
phenol catalyst A would first be deprotonated under basic
conditions to generate the colored phenolate anion B, which
could reach an electronically excited state (B*) under visible
light irradiation. On the basis of our previous work,[4] we
proposed that a single electron transfer (SET) process between
the excited phenolate anion B* and aryl halide D could occur to
produce a phenoxyl radical C and an aryl radical E. The
electrophilic aryl radical E would then undergo intermolecular
addition to an olefin acceptor F to furnish a new C-C bond and
an adjacent alkyl radical G. In the meantime, the phenoxyl
radical C could abstract a hydrogen atom from TEMPO-H (the O-
H BDFE in TEMPO-H ~ 67 kcal/mol)[13] to recycle the phenol A
(the O-H BDFE in phenol > 75 kcal/mol)[13-14] and afford the
persistent TEMPO radical. Finally, the highly selective radical-
radical cross coupling of the transient alkyl radical G with
TEMPO would be kinetically feasible to provide the desired
oxyarylation product H based on the persistent radical effect.[15]
Table 1: The model reaction and the reaction parameters evaluated.
TEMPO
catalyst (10 mol%)
TEMPOH (1.2 equiv)
+
Cs2CO3 (2.0 equiv)
DMSO (0.2 M)
light, rt
MeO
X
MeO
2
3
1a
1b
1c
, X = I
, X = Br
, X = Cl
1.5 equiv
OH
R1
R2
: R1 = R2 = R3 = H
PC1
: R1 = R2 = Ph, R3 = H
: R1 = R2 = tBu, R3 = H
: R1 = R2 = R3 = tBu
: R1 = R2 = tBu, R3 = OMe
: R1 = R2 = tBu, R3 = Ac
PC2
PC3
PC4
PC5
PC6
R3
O
Entry[a]
X
catalyst
light sources
yield
(%)[b]
R
hv
base
1
2
3
4
5
6
7
8
I
I
I
I
I
I
I
I
I
PC1
PC2
PC3
PC4
PC5
PC6
PC3
none
PC3
PC3
PC3
blue LEDs
blue LEDs
blue LEDs
blue LEDs
blue LEDs
blue LEDs
dark
blue LEDs
blue LEDs
blue LEDs
blue LEDs
40
57
87
79
73
82
0
0
0
80
42
B
H
*
O
O
O-H BDEF
> 75 kcal/mol
phenolate anion
photocatalysis
R
R
A
B
*
Ar
SET
HAT
O
N
X
O
9[c]
10
11
H
X = I, Br, Cl
R
TEMPO-H
Br
Cl
D
O-H BDEF
~67 kcal/mol
C
Ar
Ar
TEMPO
aGeneral conditions: halobenzene 1 (0.30 mmol, 1.0 equiv), 4-methoxystyrene 2
(0.45 mmol, 1.5 equiv), TEMPOH (0.36 mmol, 1.2 equiv), Cs2CO3 (0.60 mmol, 2.0
equiv), catalyst (0.03 mmol, 10 mol%), and DMSO (1.5 mL, rigorously degassed by
freeze/pump/thaw). Halobenzene 1 and TEMPOH was dissolved in DMSO and
added dropwise over 10 h. bIsolated yields by chromatography. [c] Reaction was
run in the absence of Cs2CO3.
TEMPO
Ar
R
R
aryl radiacl
E
R
F
alkyl radical
G
H
Scheme 2. Proposed photocatalytic mechanism for intermolecular radical
oxyarylation.
To evaluate these ideas, our initial exploration focused on
the oxyarylation of 4-methoxystyrene 2 with iodobenzene 1a as
2 | J. Name., 2012, 00, 1-3
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yield was achieved (entries 10 and 11). These results showed conditions employed by this reaction were proved to be
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DOI: 10.1039/D0SC02160A
that the excited state of phenolate anion was capable enough compatible with aryl halides containing a wide range of
for the reducing inert chlorobenzene.
functional groups, including unprotected -CHO (13), -COCH3
With the optimized conditions in hand, we then explored (14), -COOH (15 and 16), -OH (17 and 18), and -NH2 (19), thereby
the scope of the (hetero)aryl halides (Scheme 3, top). Iodides, eliminating the need for inefficient protection and deprotection
bromides and chlorides (regardless of the electronic properties procedures often required by traditional methodologies.
of the starting substrates) were successfully coupled to 4- Pleasingly, polycyclic aromatic hydrocarbon halides, such as
methoxystyrene 2 with good to moderate yields (412). These naphthalene (20), anthracene (21), phenanthrene (22), and
results further emphasized the strong reducing property of the fluorene (23) can also be used as radical precursors under these
excited phenolate anion of PC3. Moreover, the o- (4, 7, and 10), conditions. Last, we investigated this photocatalytic
m- (5, 8, and 11) and p- (6, 9, and 12) substituted aryl halides transformation with a variety of privileged heterocyclic motifs,
readily participated in this transformation demonstrating the which were not involved in previously known methods.
site of the substitution on the aromatic ring had no detrimental Remarkably, heterocycles such as pyridine (24 - 26), indole (27
effects on our method. It is worth highlighting that the mild - 29), quinoline (30), isoquinolone (31), pyrazine (32), thiophene
PC3
(10 mol%)
Ar
TEMPO
TEMPOH (1.2 equiv)
Ar
+
R
Cs2CO3 (2.0 equiv)
DMSO (0.2 M)
blue LEDs, rt
R
1.5 equiv
X
1.0 equiv
halide scope
TEMPO
COCH3
COOH
CHO
TEMPO
TEMPO
TEMPO
15a
TEMPO
TEMPO
CN
Me
OMe
MeO
MeO
MeO
MeO
MeO
MeO
MeO
3,
1
X = Cl, 82%, 16h
14
, X = Cl, 88%, 16h
, X = I, 80%, 16h
10
o, , X = I, 87%, 12h
X = Br, 84%, 16h
X = Cl, 77%, 24h
7
o, , X = I, 83%, 16h
X = Br, 82%, 24h
X = Cl, 48%, 36h
4
o, , X = I, 86%, 16h
X = Br, 70%, 24h
X = Cl, 42%, 36h
OH
TEMPO
TEMPO
TEMPO
11
m, , X = I, 82%, 12h
8
m, , X = I, 87%, 16h
5
m, , X = I, 82%, 16h
COOH
OH
X = Br, 85%, 16h
X = Cl, 75%, 24h
p, , X = I, 85%, 12h
X = Br, 85%, 24h
X = Cl, 45%, 36h
X = Br, 76%, 24h
X = Cl, 40%, 36h
MeO
MeO
12
9
p, , X = I, 86%, 16h
6
p,
,
X = I, 87%, 16h
X = Br, 82%, 24h
X = Cl, 38%, 36h
X = Br, 83%, 16h
X = Cl, 75%, 24h
X = Br, 82%, 24h
X = Cl, 55%, 36h
16a
, X = I,82%, 16h
17a
18
, X = I, 84%, 16h
,
X = I,77%, 20h
NH2
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
N
MeO
MeO
MeO
24
MeO
MeO
MeO
MeO
19
20
21
22
23
, X = Br, 55%, 36 h
,
X = I, 65%, 20h
, X = Br, 80%, 24h
, X = Br, 65%, 24h
, X = I, 88%, 16h
, X = I, 74%, 12h
TEMPO
H
N
N
NBoc
TEMPO
TEMPO
TEMPO
TEMPO
N
TEMPO
N
N
H
MeO
25
MeO
26
MeO
MeO
MeO
27
28
29
30
, X = I, 66%, 16h
, X = I, 83%, 12h
, X = I, 55%, 16h
, X = I, 81%, 20h
, X = I, 73%, 16h
, X = I, 40%, 16h
Ph
N
N
N
N
O
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
S
S
MeO
33
MeO
34
MeO
MeO
31
MeO
32
MeO
35
36
, X = I, 83%, 16h
, X = Br, 91%, 16h
, X = I, 54%, 16h
, X = I, 62%, 16h
, X = Br, 65%, 36h
, X = Br, 64%, 36 h
olefin scope
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
N
MeO2C
40
tBu
38
Ph
,
X = I, 71%, 16h
37
39
41
42
, X = I, 86%, 16h
, X = I, 83%, 16h
, X = I, 87%, 16h
OMe
, X = I, 91%, 16h
, X = I, 91%, 16h
N
O
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
N
TsHN
43b
44b
45b
46b
47b
48b
, X = I, 54%, 16h
, X = Br, 52%, 16h
, X = Cl, 56%, 16h
, X = I, 61%, 16h
TEMPO
, X = Br, 67%, 16h
N
, X = I, 42%, 16h
N
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
HO
N
O
O
BocN
49b
50b
51b
52b
53b
54b
, X = Br, 75%, dr > 98:2, 16h
, X = I, 61%, 16h
, X = I, 68%, 16h
, X = I, 60%, 16h
, X = I, 51%, dr > 98:2, 16h
, X = Br, 81%, 16h
intramolecular
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
N
N
N
O
O
O
Ac
Ac
Ac
55
56
57
58
59
60
, X = I, 87%, dr > 98:2, 16h
, X = I, 82%, 16h
, X = I, 79%, 16h
, X = I, 85%, 16h
, X = I, 80%, 16h
, X = I, 90%, dr > 98:2, 16h
Scheme 3. Reaction scope. General conditions: (hetero)aryl halide (0.30 mmol, 1.0 equiv), olefin (0.45 mmol, 1.5 equiv), TEMPOH (0.36 mmol, 1.2 equiv), Cs2CO3 (0.60
mmol, 2.0 equiv), PC3 (0.03 mmol, 10 mol%), and DMSO (1.5 mL, rigorously degassed by freeze/pump/thaw). (Hetero)aryl halide and TEMPOH was dissolved in DMSO
b
and added dropwise over 10 h. Isolated yields were reported. aWith 3 equiv of the Cs2CO3. With 3 equiv of the olefin.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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(33) thianaphthene (34), benzofuran (35) and carbazole (36) TEMPO-derived oxyarylation productsDO(IS: c10h.e10m39e/D04SaC)0.216F0oAr
were found to be efficient coupling partners in our reaction instance, cleavage of the N-O bond in alkoxyamine 3 with Zn in
system.
acetic acid afforded the alcohol 61, oxidation of alkoxyamine 3
We next surveyed the scope of olefin acceptors that could smoothly proceeded to provide ketone 62 with m-
be used for the current transformation (Scheme 3, middle). chloroperoxybenzoic acid (MCPBA) in DCM, and radical
Using iodobenzene 1a as a model aryl halide, various styrene deoxygenation occurred by heating alkoxyamine 3 in the
derivatives were effectively converted to the corresponding presence of thiophenol to deliver compound 63.[8a] In addition,
oxyarylation products 3742 in good to excellent yields under alkoxyamine 3 is also an ideal carbocation precursor in Ir-
the standard conditions. Furthermore, this oxyarylation method catalyzed alkoxyamine radical cation mesolytic cleavage
was not only limited to aryl olefins; non-activated aliphatic reaction, and the resulting carbocation intermediate can be
olefins were also found to be compatible with this reaction trapped by different nucleophiles such as cyclohexanol, TMSN3,
system (4352). We observed that a series of representative and indole to afford a series of useful molecular architectures
(hetero)aryl halides were successfully coupled to 1-hexene to 6466.[16] Finally, we evaluated our method for late-stage
give the desired products 4347 with synthetically useful yields. functionalization applications (Scheme 4b). Pharmaceutical
To our delight, allylic sulfonamide (48) and alcohol derivatives ingredients (fenofibrate, furosemide, glibenclamide, and
(49) were also readily accommodated under these reaction hydrochlorothiazide) that contained an aryl chloride were
conditions. In addition, the 1,1- or 1,2- disubstituted olefins effectively converted into corresponding oxyarylation products
were found to be competent coupling partners and provided 6770 in 61% - 77% yield, further highlighting the utility of our
the desired products with acceptable yields (5052). Further method in a complex setting.
studies revealed that enol ethers were also suitable substrates
and yielded the oxyarylation products 53 and 54 in good yields.
3.0
a
1.0
b
Subsequently, we found that intramolecular variants of this
transformation were successful, and a variety of aryl iodides
cyclized under our photocatalytic system to deliver a range of
five- and six-membered heterocyclic products 5560 (Scheme
3, bottom).
2.5
0.8
no 1a added
[1a] = 0.01M
[1a] = 0.02M
[1a] = 0.03M
[1a] = 0.04M
2.0
1a
PC3
PC3+Cs2CO3
0.6
0.4
0.2
0.0
1.5
1.0
0.5
0.0
1a+PC3+Cs2CO3
250
300
350
400
450
500
550
600
400
450
500
550
600
Wavelength (nm)
Wavelength (nm)
a) Chemical Transformations of alkoxyamine 3
c
1.0
1.0
0.8
0.6
0.4
0.2
0.0
0.00008
0.00006
0.00004
0.00002
0.00000
-0.00002
-0.00004
-0.00006
d
OH
0.8
0.6
0.4
0.2
0.0
E1/2 = -0.10 V
cyclohexanol, IrIII
O
Zn
AcOH, H2O
blue LEDs, MeNO2
absorbance
emisson
MeO
MeO
61
, 96%
MeO
64
, 95%
405 nm
TEMPO
O
N3
-1.0
-0.8
-0.6
-0.4
-0.2
0.0
0.2
0.4
TMSN3, IrIII
300
400
500
600
mCPBA
DCM
MeO
Potential (V vs. SCE)
Wavelength (nm)
blue LEDs
MeNO2
MeO
Figure 1. a, UV/Vis absorption spectra of DMSO solutions (0.10 M) of 1a, PC3,
mixture of PC3 and Cs2CO3, and mixture of 1a, PC3 and Cs2CO3. b, Quenching of
the phenolate of PC3 emission (5 × 10-5 M in DMSO) in the presence of increasing
amounts of 1a. c, The cyclic voltammogram of the phenolate anion of PC3 vs SCE
in DMSO at 0.1 V/s. d, Normalized absorption and emission spectra of the
phenolate anion of PC3 in dry DMSO (5 × 10-5 M), the intersect wavelength was
considered to be 405 nm.
3
62
, 95%
65
, 87%
NH
H
indole, IrIII
blue LEDs, MeNO2
PhSH
tBuPh, 120 o
C
MeO
63
, 90%
MeO
As a means of illuminating the mechanism of this
proposed photocatalytic transformation, a number of UV-vis
experiments were conducted (Figure 1a). In analogy with our
previous studies,[4] we found that the colorless solution of PC3
(orange line in Figure 2a) was immediately turned to a primrose
yellow color upon addition of Cs2CO3 (blue line in Figure 2a, the
absorption of the phenolate anion of PC3) and did not observe
any color change when iodobenzene 1a was added to the
solution of phenolate anion of PC3 (red line in Figure 2a,
perfectly overlapped with the absorption of the phenolate
anion of PC3). These results excluded the formation of a
ground-state EDA complex between the phenolate anion and
aryl halide and indicated that the excited phenolate anion was
responsible for triggering the aryl radical from its halide.[3, 17]
Further support for this conclusion was obtained from Stern-
Volmer quenching studies (Figure 1b), in which the excited state
of the phenolate anion of PC3 was effectively quenched by
66
, 93%
b) Late-stage modification of pharmaceuticals
O
NH
O
O
TEMPO
TEMPO
OH
O
O
O
MeO
SO2NH2
MeO
Fenofibrate: X = Cl
67, 68%, 20h
Furosemide: X = Cl
68, 77%, 20h
OMe
H
N
HN
NH
SO2
TEMPO
TEMPO
O
O
O
MeO
S
N
NH
SO2NH2
O
H
MeO
Glibenclamide: X = Cl
69, 61%, 20h
Hydrochlorothhiazide: X = Cl
70, 71%, 20h
Scheme 4. Synthetic applications of this photocatalytic oxyarylation reaction. a,
Chemical transformations of alkoxyamine 3. b, Late-stage modification of
pharmaceuticals.
To expand the synthetic value of this method, we
investigated the further chemical manipulation of these
4 | J. Name., 2012, 00, 1-3
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iodobenzene 1a. Moreover, a decline in the excited state pathway to give the carbocation and then is trapped by the
View Article Online
DOI: 10.1039/D0SC02160A
lifetime also was observed in the time-resolved quenching TEMPOH alcohol to afford the oxyarylation product. In order to
studies, and the Stern-Volmer analysis revealed a linear exclude the possible SET pathway between the benzyl radical
correlation indicating a dynamic quenching of the excited and the phenoxy radical, 2-iodophenylmethanol 74 was chosen
phenolate anion of PC3 by 1a (see ESI Note 5†).[12b] In addition, as a substrate to trap the carbocation intermediate by the
the thermodynamic feasibility of the photoinduced SET was intramolecular alcohol (Scheme 6). If the carbocation 76 was
analyzed by the oxidation-reduction potentials. The ground- generated by SET process with phenoxyl radical (path b), an
state potential E1/2(PC3̇
/PC3-) was determined to be -0.10 V vs. intermolecular cyclization will follow to give product 77.
SCE (Figure 1c) and the excited-state energy E0-0(PC3-*/ PC3-) However, only the intermolecular oxyarylation product 78 was
was read from the intersection of the normalized absorbance obtained in 85% yield without any formation of intramolecular
and emission spectra at 405 nm as 3.06 eV (Figure 1d).[18] cyclization product 77. Instead, the alkoxyamine 78 was
Therefore, the redox potential of the excited phenolate anion efficiently cyclized to provide 77 in 92% yield through a
of PC3 was calculated to be -3.16 V vs. SCE (E1/2(PC3
E1/2 (PC3
/ PC3-) – E0-0(PC3-*/ PC3-)), which indicated that the radical cation mesolytic cleavage reaction,[16] confirming that
̇
/ PC3-*) = carbocation intermediate in the Ir-catalyzed alkoxyamine
̇
reduction of iodobenzene 1a (-2.24 V vs. SCE), bromobenzene the cyclization could easily take place if the carbocation 76 was
1b (-2.44 V vs. SCE), and even chlorobenzene 1c (-2.78 V vs. SCE) generated. These results implied that the radical-radical cross
by the excited phenolate anion of PC3 is thermodynamically coupling of the benzyl radical with the HAT product TEMPO to
feasible.[19] To further probe whether the singlet excited state provide the desired oxyarylation product would be more
of the phenolate anion of PC3 could be responsible for the plausible.
catalysis in our system, an oxygen tolerance experiment was
PC3
(10 mol%)
O
performed open to air (Scheme 5a). Under these conditions,
where triplet pathways should be inhibited by oxygen (a potent
triplet quencher),[20] a 72% yield was still observed after 16 h.
These results indicated that the singlet state may be the primary
mode of catalysis, but the combination catalysis of singlet and
triplet states in our system cannot be completely ruled out at
this time.[20b]
TEMPOH (1.2 equiv)
+
Cs2CO3 (2.0 equiv)
DMSO (0.2 M)
blue LEDs, 16h, rt
MeO
1.5 equiv
I
OH
MeO
2
77
74
1.0 equiv
OH
TEMPO
IIIblue
Ir
MeNO
2,
LEDs
MeO
TEMPO
92%
a
78
, 85%
path
OH
OH
a
PC3
TEMPO
(10 mol%)
phenoxyl radical
TEMPOH (1.2 equiv)
+
path b, SET
Cs2CO3 (2.0 equiv)
DMSO (0.2 M)
blue LEDs, 16h, rt
air
MeO
1.5 equiv
I
MeO
MeO
MeO
2
75
76
1a
1.0 equiv
3
, 72%
Scheme 6. Intramolecular carbocation trapping experiments.
b
PC3
(10 mol%)
N
O
Cs2CO3 (2.0 equiv)
+
N
O
DMSO (0.2 M)
Conclusions
blue LEDs, 16h, rt
I
H
1a
1.0 equiv
1.2 equiv
In conclusion, the phenolate anion was discovered as a
new photocatalyst under visible light and enabled the
intermolecular oxyarylation of olefins with aryl and heteroaryl
halides. This process utilized stable and readily available
halogenated arenes as radical precursors, avoided the use of
sacrificial reductants, and exhibited broad functional group
tolerance. Moreover, the developed three-component coupling
reaction was further applied to the late-stage modification of
active pharmaceutical ingredients, and the resulting TEMPO-
derived oxyarylation products are ideal precursors for
diversified chemical manipulations to afford a series of useful
molecular architectures. The high reducing character of this
photocatalytic system together with the mild reaction
conditions will open new avenues for the development of aryl
radical-based transformations.
71
, 53%
TEMPO
c
PC3
(10 mol%)
TEMPOH (1.2 equiv)
+
Cs2CO3 (2.0 equiv)
DMSO (0.2 M)
blue LEDs, 16h, rt
I
1a
1.0 equiv
72
1.5 equiv
73
, 59%
Scheme 5. a, Oxygen tolerance experiments. b, Controlled experiments without
4-methoxystyrene. c, Radical clock experiments.
To support the radical mechanism suggested in scheme 2,
we performed several mechanism experiments. In the absence
of 4-methoxystyrene, the reaction provided TEMPO-Ph (71) in
53% yield (Scheme 5b), proving that a phenyl radical along with
a TEMPO were formed under reaction conditions. We then
investigated the radical clock experiments with α-
cyclopropylstyrene (72) and found that the ring-opened adduct
73 was obtained in 59% yield (Scheme 5c).These results strongly
suggested the formation of
intermediate.[21]
a benzyl radical as the
Conflicts of interest
Besides the proposed pathway of coupling between alkyl
radical and TEMPO as shown in scheme 2, it is also possible that
the alkyl radical is firstly oxidized by the phenoxyl radical in SET
There are no conflicts to declare.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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Journal Name
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Seath, A. M. Zearfoss, Z. Xu, N. T. Jui, J. Am. Chem. Soc. 2019,
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Acknowledgements
This work was financially supported by the Natural Science
Foundation of Yunnan Province (2018FY001015), China
Postdoctoral Science Foundation (2018M643540), the National
Natural Science Foundation of China (21871228), and the
Program for Changjiang Scholars and Innovative Research Team
in University (IRT_17R94).
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6 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/D0SC02160A
Graphic Abstract
The phenolate anion was developed as a new photocatalyst with strong reducing
potentials (-3.16 V vs. SCE). The activated phenolate anion enabled the reduction of
(hetero)aryl halides to (hetero)aryl radicals through single electron transfer. A novel
and efficient protocol for the intermolecular oxyarylation of olefins with aryl halides
and TEMPOH was developed with the new photocatalyst.
R
O
TEMPO
Reducing Potentials -3.16 V
TEMPO-H
Ar
Ar
X = I, Br, Cl
X
+
R
R